Caspases are a family of cysteine protease enzymes that are key mediators in the signaling pathways for apoptosis and cell disassembly (Thornberry, Chem. Biol., 1998, 5, R97-R103). Apoptosis, or programmed cell death, is a principal mechanism by which organisms eliminate unwanted cells. The deregulation of apoptosis, either excessive apoptosis or the failure to undergo it, has been implicated in a number of diseases such as cancer, acute inflammatory and autoimmune disorders, and certain neurodegenerative disorders (see generally Science, 1998, 281, 1283-1312; Ellis et al., Ann. Rev. Cell. Biol., 1991, 7, 663). Caspase-1, the first identified caspase, is also known as interleukin-1β converting enzyme or “ICE.” Caspase-1 converts precursor interleukin-1β (“pIL-1β”) to the pro-inflammatory active form by specific cleavage of pIL-1β between Asp-116 and Ala-117. Besides caspase-1 there are also eleven other known human caspases which have been classified into families based on their biological function.
A number of useful caspase inhibitors have been reported that contain an aspartic acid aldehyde moiety, which will exist in equilibrium with its cyclic hemiacetal form as shown below:
where W2 represents the rest of the caspase inhibitor molecule. Based on the hemiacetal, orally available prodrugs of these inhibitors have been developed having the acetal structure 1, including the compound 2 in which R1 is alkyl. The ICE inhibitor 2 is a prodrug being developed as a treatment for rheumatoid arthritis (see U.S. Pat. No. 5,716,929).

Processes for the preparation of a peptidic caspase inhibitor prodrug of formula 1 have been reported (see, e.g., Bioorg. Med. Chem. Lett. 1992, 2(6), 613 and WO 99/03852. However, reported routes have disadvantages, especially for preparing chiral compounds. For example, the routes require expensive starting materials, chromatographic separation of diastereomers, and/or disadvantageous synthetic steps.
It would be desirable to have a synthetic route to aspartic acetal caspase inhibitors, or prodrugs thereof, that is amenable to large-scale synthesis and overcomes the aforementioned shortcomings or otherwise improves upon the current methods.